Summary

Introduction

The incidence of steroid-refractory graft versus host disease (SR-GVHD) is a one-half of patients with a mortality rate of 70%. Janus kinase (JAK) 1/2 inhibitors might be considered as a salvage therapy. However, there is a scarcity of relevant information about optimal duration and taping strategy of Jak-2-inhibitors. Our aim was to present a clinical case of a liver SR-GVHD after haploidentical HSCT (haplo-HSCT) in a young patient with Gilbert syndrome who developed decrease of liver function tests following discontinuation of Jak-2 kinase inhibitor therapy. Medical records, laboratory and instrumental data were reviewed when analyzing the results. GVHD severity was scored according to the 2014 NIH Consensus Criteria.

Case report

A 28-year-old male patient with acute myeloid leukemia (AML), FAB-M2, and concurrent Gilbert syndrome underwent haplo-HSCT on 12 May 2015 from brother, HLA compatibility, 6/10. Conditioning regimen: busulfan 8 mg/kg, fludarabine. Bone marrow was a source of stem cells:. GVHD prophylaxis: cyclophosphamide (30 mg/kg, days+3,+4), tacrolimus (from day+5), mycophenolate mofetil (45 mg/kg, days from +5 to +35). On day+90, tacrolimus was discontinued due to early bone marrow recurrence. On day+202, overlap-syndrome of grade 4 was developed, with skin, liver and lower gastrointestinal tract (GIT) lesions (grade 3, 4 and 3 respectively). The first-line therapy: methylprednisolone 2 mg/kg, causing partial response for skin. Etanercept (25 mg twice a day) and tacrolimus were added, followed by complete response for skin and GIT; bilirubin level was >250 μmol/L. The immunosuppressive therapy was discontinued on the day+237, due to pulmonary hemorrhage and transfer to intensive care unit. Increased bilirubin level (580 μmol/L) and intestinal bleeding were observed. This treatment was replaced by a Jak-2 inhibitor (ruxolitinib, 20 mg per day). The effect: decreased bilirubin level, without any dynamics for intestinal pathology. On day+249, fecal microbiota transplantation was performed, followed by resolution of GI symptoms. Mesenchymal stem cells were infused twice (D+257, D+266) with no response. Cholesterol levels raised over 40 mmol/L, having been treated bi-weekly plasmapheresis. From day+316 to day+426, the patient received 5 infusions of tocilizumab, he underwent 12 courses of extracorporeal photopheresis, sirolimus and low-dose interleukin-2, without any response (bilirubin 520 to 724 μmol/l). On day +350, liver biopsy was performed, and GVHD pathology was detected. Sirolimus and ruxolitinib were administered from day+460 to day+738. Ruxolitinib was replaced by a new-generation Jak-2 kinase inhibitor baricitinib (4 mg daily) on day+738. The following effect was observed: bilirubin level 220-420 mmol/L, hypercholesterolemia still persisted. On day+1120, baricitinib was discontinued. Further on, a decrease of bilirubin (213 μmol/L) and cholesterol levels (7.7 mmol/l) were documented. The therapy with sirolimus is going on, and significant improvement in the quality of life is noted.

Conclusion

Steroid-refractory severe chronic liver GVHD is a condition that might require prolonged immunosuppressive treatment with absence of complete response to current treatments. Despite high efficacy of JAK-2-inhibitors, they might be associated with serious adverse effects, like severe hypercholesterolemia. Gilbert syndrome may complicate the assessment of GVHD response and require liver biopsy to guide a therapy.